Citalopram is a well-known antidepressant drug that has the following structure:

It is a selective, centrally active serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly having antidepressant activities.
Citalopram was first disclosed in DE 2,657,013, corresponding to U.S. Pat. No. 4,136,193. This patent publication describes the preparation of citalopram by one method and outlines a further method, which may be used for preparing citalopram. The citalopram prepared was isolated in crystalline form as the oxalate, the hydrobromide and the hydrochloride salt, respectively. Furthermore, the citalopram base was obtained as an oil (B.P. 175° C./0.03 mmHg). The publication also outlines the manufacture of tablets containing salts of citalopram. Citalopram is marketed as the hydrobromide and the hydrochloride, respectively.
Escitalopram, the pharmaceutical activity thereof and crystalline escitalopram oxalate are disclosed in U.S. Pat. No 4,943,590. Methods for preparation of pharmaceutical preparations of escitalopram are outlined.
Citalopram is marketed in a number of countries as a tablet prepared by compression of granulated citalopram hydrobromide, lactose and other excipients.
It is well recognised that preparation of tablets with a reproducible composition requires that all the dry ingredients have good flow properties. In cases, where the active ingredient has good flow properties, tablets can be prepared by direct compression of the ingredients. However, in many cases the particle size of the active substance is small, the active substance is cohesive or has poor flow properties.
Further, active substances with a small particle size mixed with excipients having a larger particle size will typically segregate or de-mix during the tabletting process.
The problem of small particle size and poor flowability is conventionally solved by enlarging the particle size of the active substance, usually by granulation of the active ingredient either alone or in combination with a filler and/or other conventional tablet ingredients.
One such granulation method is the “wet” granulation process. Using this method, the dry solids (active ingredients, filler, binder etc.) are blended and moistened with water or another wetting agent (e.g. an alcohol) and agglomerates or granules are built up of the moistened solids. Wet massing is continued until a desired homogenous particle size has been achieved whereupon the granulated product is dried.
An alternative to the “wet” granulation method is the “melt” granulation, which is also known as the “thermal plastic” granulation process, where a low melting solid is used as the granulation agent. Initially, the dry solids are blended and heated until the binder melts. As the binder is liquefied and spreads over the surface of the particles, the particles will adhere to each other and form granules. The binder solidifies upon cooling forming a dry granular product.
Wet granulation as well as melt granulation are energy intensive unit operations requiring complicated and expensive equipment as well as technical skill.
If the active ingredient, however, has suitable flow properties, then the granulation step can be avoided and tablets may be prepared by direct compression which is a cheaper production method.
The process used for the preparation of citalopram hydrobromide results in a product with a very small particle size around 2-20 μm that, as many other particulate products with a small particle size, has very poor flow properties. Thus, in order to achieve appropriate dosing of the citalopram hydrobromide during tabletting, it was considered necessary to make a granulate of citalopram hydrobromide with larger particle size and improved flow properties.
The citalopram tablet that is marketed is a tablet made from granulated citalopram hydrobromide with various excipients.
We have found that escitalopram has significantly different solubility and salt formation properties from the citalopram racemate. For example, the only pharmaceutically crystalline salt known so far is the oxalate, whereas the citalopram racemate forms crystalline hydrobromide and hydrochloride salts as well.
The escitalopram oxalate product prepared by crystallisation from acetone as outlined in U.S. Pat. No 4,943,590 has, as the citalopram hydrobromide product described above, a very small particle size around 2-20 μm resulting in similarly poor flow properties.
WO03/000672 discloses a process for the preparation of racemic as well as enantiomerically pure citalopram from the compound R-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile by ring-closure under acidic conditions.
WO03/011278 discloses crystalline particles of escitalopram oxalate with a particle size of at least 40 μm. Method for the manufacture of said crystalline particles and pharmaceutical compositions comprising said crystalline particles are also disclosed.
The inventors of the present invention have now surprisingly realised that the particle sizes obtained if escitalopram prepared according to the process disclosed in WO03/000672 is precipitated as the oxalate salt according to the method disclosed in WO03/011278, are significantly smaller than those obtained from prepared by ring-closure of S-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxy-methyl)-benzonitrile via a labile ester under alkaline conditions.
They have furthermore realised that the reduction in particle size of the escitalopram oxalate crystals is related to the presence of a specific impurity, Z-4-(4-dimethyl-amino-1-(4-fluorophenyl)-but-1-enyl)-3-hydroxymethyl-benzonitrile. This impurity is unique for the acidic ring-closure process as compared to the ring-closure via a labile ester under alkaline conditons.
In view of the fact that direct compression is much simpler and cheaper than the processes involving granulation there is a continued desire for large crystals of escitalopram or pharmaceutical acceptable addition salts thereof.
Laboratory and full-scale research have now resulted in a new and inventive process producing large crystalline particles of escitalopram oxalate, i.e. particles of a size comparable to the size of the filler, by a novel and inventive process for reduction of the amount of Z-4-(4-dimethylamino-1-(4-fluorophenyl)-but-1-enyl)-3-hydroxymethyl-benzonitrile in the solution of escitalopram prior to crystallisation of the oxalate. Said particles are useful for the manufacture of directly compressed tablets. Accurate dosing in capsules may also be with such large particles.